Thursday, June 24, 2010

It's not just for headaches anymore! The active ingredient in TYLENOL® (acetaminophen, also known as paracetamol) has been shown to ease the pain of social rejection. Wouldn't it be great if you could pop an over-the-counter medication to lessen the hurt of being excluded from that grad student party? Of being ostracized by all your old friends? Even disowned by your family and becoming homeless? The journal article, which was promoted by press release six months ago, has finally appeared online (Dewall et al., 2010). An excerpt from the December 2009 press release is below.

“The idea—that a drug designed to alleviate physical pain should reduce the pain of social rejection—seemed simple and straightforward based on what we know about neural overlap between social and physical pain systems. To my surprise, I couldn’t find anyone who had ever tested this idea,” [psychologist C. Nathan]DeWall said.

Perhaps because there's no clear mechanistic basis for such an idea? The authors themselves never proposed one either. One might expect that a psychopharmacological experiment with a drug that can cause serious liver damage would be conducted with a specific hypothesis in mind and some basic knowledge about how the drug is thought to work, but we didn't see that here. Granted, that would not be typical fare for Psych Sci. So instead the rationale given by Dewall et al. (2010) is partially linguistic, partially based on a neuroimaging study (Eisenberger et al., 2003):

Studies suggest that the similar linguistic descriptions of social and physical pain extend beyond metaphor, and demonstrate overlap in the neurobiological systems underlying physical pain and social pain (DeWall & Baumeister, 2006;Eisenberger, Lieberman, & Williams, 2003; Way, Taylor, & Eisenberger, 2009). In the present experiments, we examined one functional consequence of the hypothesis that social and physical pain rely on shared neurobiological systems—whether acetaminophen, a common physical pain reliever, also reduces social pain.

The "shared neurobiological systems" are thought to be located in the dorsal anterior cingulate cortex (ACC), a brain structure that contains discrete regions responsive to physical pain (Kwan et al., 2000). Interestingly, externally applied vs. self-administered thermal pain activate anatomically distinct areas of the ACC (Mohr et al., 2005). Furthermore, it is not at all clear whether the same regions of ACC represent social pain and the affective components of physical pain. In a study designed to dissociate expectancy violations from social rejection, the dorsal ACC was activated when expectations were violated, while ventral ACC (quite distant from the physical pain regions) was activated by social rejection (Somerville et al., 2006).

Figure 2 (Somerville et al., 2006). Differential ACC response to expectancy violation and social feedback. (a) A three-dimensional rendering of the medial surface of the brain illustrates a functional dissociation between dorsal (dACC) and ventral (vACC) anterior cingulate. A whole-brain voxel-by-voxel ANOVA was used to identify voxels that showed a significant main effect (P less than 0.001, uncorrected) of expectancy violation (blue) and a main effect of feedback type (yellow).

At any rate, participants in the Eisenberger et al. (2003) study took part in a computerized ball-tossing game while being scanned. Initially, two fictitious players included the scanned subject in the game, but then started to exclude him/her. This was the “social exclusion” condition, which was compared to the inclusion condition. But it happens to be the case that this paper was singled out as one of the worst of the "voodoo correlation" violators by Vul and his colleagues[PDF], since it reported a statistically unlikely value based on a non-independent analysis:

Eisenberger, Lieberman, and Williams (2003), writing in Science, described a game they created to expose individuals to social rejection in the laboratory. The authors measured the brain activity in 13 individuals at the same time as the actual rejection took place, and later obtained a self-report measure of how much distress the subject had experienced. Distress was correlated at r=.88 with activity in the anterior cingulate cortex (ACC).

That brings us to the present study by Dewall et al. (2010). In Experiment 1, 30 participants (24 women, 6 men) took one 500 mg acetaminophen pill immediately after waking up and another 500 mg an hour before going to sleep (1,000 mg per day for 3 weeks). The other 32 participants (24 women, 8 men) took the same dosing of placebo for 3 weeks. Each evening, subjects filled out the the Hurt Feelings Scale (the "today" version) to report how much social pain they had experienced that day. Despite the fact that the half life of acetaminophen is 4 hours, it took about 10 days for the drug group to report significantly lower hurt feelings than the placebo group. The difference on day 21 was greatest (p < .005). However, the difference in change-over-time slopes between the two groups was only marginally significant (p ≤ .10). The explanation of the time course for these effects was unclear:

Acetaminophen has a relatively short half-life, lasting approximately 4 hr, which means that it is unlikely that acetaminophen had a cumulative effect in our experiments. Our finding that acetaminophen reduced hurt feelings over time could be due to a combination of not feeling hurt and having a greater ability to reappraise the rejection experience.

In Experiment 2, the dose was upped to 2,000 mg acetaminophen per day for 3 weeks. Instructions were given to refrain from drinking entirely, since alcohol can potentiate liver damage when taken with acetaminophen. In 2009, an FDA panel made a recommendation to lower the maximum daily dose from 4,000 mg (to an unspecified value). The panel also endorsed limiting the maximum single dose of the drug to 650 mg, down from the current 1,000 mg dose (which was given in Exp. 2). At the end of the three week period, the cyberball exclusion fMRI study was run. The acetaminophen group showed less activity in dACC in response to social exclusion, but they did not report lower hurt feelings.

Hmm. As an aside, here's another puzzling observation. If it's been claimed that "social exclusion hurts" (Macdonald & Leary, 2005), then why does the experience of social exclusion result in higher tolerance for physical pain and higher pain thresholds (DeWall & Baumeister, 2006)?

Next, I have a series of questions for the authors:

Did you consider the negative consequences of acetaminophen?

Did your IRB have anything to say about this (there was NO info in the paper on institutional approval or the signed consent procedure with participants)?

How did you decide on your dosing regimen?

Why 3 weeks, when the half-life is only 4 hrs?

Instructions say "do not use for more than 10 days without doctor's permission." Was an MD involved in the study?

And most critically, why did you choose acetaminophen, rather than aspirin, ibuprofen, or naproxen?

Related to this, why did the first version of the manuscript have "Tylenol" in the title? 1

I was also alarmed by the wild extrapolation from exclusion in a laboratory video game to purported increases in aggressive violence:

Furthermore, many studies have shown that being rejected can trigger aggressive and antisocial behavior, which could lead to further complications in social life (DeWall, Twenge, Gitter, & Baumeister, 2009; Warburton, Williams, & Cairns, 2006). If acetaminophen reduces the distress of rejection, the behavioral consequences of rejection, such as antisocial behavior, may be reduced as well. Indeed, our fMRI results showed that acetaminophen diminished reactivity in the dACC and amygdala, brain regions that have been linked to aggression (Denson, Pedersen, Ronquillo, & Nandy, 2009; Eisenberger, Way, Taylor, Welch, & Lieberman, 2007). It would therefore be worthwhile to explore whether acetaminophen reduces the aggressive consequences of social rejection.

I'm sure the 24 women in the placebo condition felt like committing mass murder after being excluded from a game of cyberball. Better put them on TYLENOL®.

The Medscape article on the study had prominent kudos from Bruce G. Charlton, MD, who:

...applauded the investigators' research efforts.

"It is particularly difficult to get research funding to study old, cheap, unpatented, over-the-counter drugs, so I congratulate the authors on doing this," he said.

Dr. Charlton, who [was] editor-in-chief of Medical Hypotheses and professor of theoretical medicine at the University of Buckingham, United Kingdom, agreed that different sorts of pain are often related, so there is good reason to assume that acetaminophen or paracetamol may benefit those who suffer any type of pain of unpleasant feelings, including some types of depression.

However, he noted that the same effect would likely apply to aspirin, nonsteroidal anti-inflammatory drugs, and opiates, "about which there is more evidence," he said.

One last question arose when I checked funding for the study:

This work was funded by grants from the National Institute of Mental Health (MH-65999) and the Gulf Atlantic Group, Inc.

DeWall, C. N. (2008). Effects of Daily Acetaminophen on Social Emotions: Can Two Tylenol Overcome Heartbreak? Paper presented at the Annual Meeting of the Society of Personality and Social Psychology. Albuquerque, NM.

Sunday, June 13, 2010

50 First Dates maintains a venerable movie tradition of portraying an amnesiac syndrome that bears no relation to any known neurological or psychiatric condition (Baxendale, 2004).

That isn't true anymore...

Smith et al. (2010) have recently reported an unusual case of functional, or psychogenic amnesia in which FL, a 51 year old woman with 15 years of education and average intelligence, cannot remember what happened to her from one day to the next. Her case history is summarized below.

In May 2005, FL was involved in a motor vehicle accident in which her car was struck from behind. She hit the left side of her head and briefly lost consciousness. She was treated and released from the emergency room, but upon awakening the next morning, she had no memory for the previous day and believed that the accident had just occurred. Every morning since has been similar. She awakens with anxiety, believes it to be the day of the accident, and states that she has no memory for anything that has occurred since the accident. Each morning her husband orients her to time and place and provides her with her journal where she has recorded salient events from previous days and weeks. During the course of the day, she describes her memory as normal, but states that memory for each day is lost at night during sleep.

The plot summary for 50 First Dates, taken from Wikipedia, is as follows:

One morning, Henry (Sandler) meets Lucy Whitmore (Barrymore), a local art teacher, in a café. They hit it off and agree to meet the next day, but when Henry returns, Lucy has no memory of him or their previous meeting. Pulling him aside to where Lucy can't hear them, the café owner explains to Henry that, as a result of a car accident a year earlier, Lucy suffers from Goldfield Syndrome, a fictional form of anterograde amnesia in which each day's events disappear from her memory overnight.

FL reported she did not see the movie before her accident, but noted that Drew Barrymore was her favorite actress. Smith et al. (2010) speculated that FL could have known the plot of the film, which could have influenced her unusual manifestation of memory loss after the auto accident. Her husband mentioned that she had seen the movie several times since her accident.

FL underwent a series of imaging and neuropsychological tests in Dr. Larry Squire's Memory Research Laboratory. Her MRI was read as normal by the neuroradiologist, and quantatitive analysis revealed the volumes of her medial temporal lobe structures [critical for forming new memories] to be quite well matched with a small group of control participants.

Fig. 1 (Smith et al., 2010). (A) A T1-weighted coronal MRI image from FL. The left side of the brain is on the left side of the image. (B) The volume of bilateral hippocampus (HIP) and parahippocampal gyrus (PHG) were similar for FL and controls (n = 4). The volumes are expressed as a percentage of the whole-brain volume for each participant.

FL's neurological exam was normal. She had no previous history of psychiatric disorder. On the basis of these negative neurological and MRI findings, combined with her neuropsychological profile, the psychiatrist diagnosed psychogenic [i.e. functional] amnesia, with one unusual difference: she did not have retrograde amnesia[memory loss for remote events].

Although functional amnesia is not associated with structural brain damage, there is evidence of hypometabolism, especially in the frontal lobe as measured by neuroimaging. Similar findings have also been observed in other psychiatric and neurological conditions (i.e., transient global amnesia, bipolar and major depressive disorder, schizophrenia).

The pattern of impairment in functional amnesia is variable, though it typically presents as severe retrograde amnesia (sometimes including loss of personal identity) in the absence of anterograde amnesia[problems encoding new memories].

However, FL was impaired on some standardized neuropsychological measures of memory when tested the same day, which belied her claim of intact memory for events occurring within a day. But as expected, she was at chance performance for material tested 24 hrs later, after she had slept.

The authors constructed a tricky memory test of their own to see whether FL could retain some memory for items she had learned 24 hrs ago but believed to be presented on the same day. This did work to some extent, as shown in the black bars for FL on the left (Next-day Covert).

Fig. 2 (Smith et al., 2010). Recognition memory for color photographs of scenes. One presentation: FL, Controls (n = 3), and Simulators (n = 2) [asked to fake an amnesia like FL's] saw 160 scenes once each and then took recognition memory tests later on the same day (Same day) as well as on the morning of the next day (Next day). After the Next-day test, participants studied 160 new scenes and then took recognition memory tests later on the same day. In this case, unbeknownst to the participants, the retention tests included scenes that had been studied and tested on the previous day (Next-day Covert). Multiple Presentations: the same scenes that had been studied and tested during the first 2 days were studied an additional time. As above, testing was done in three ways (Same day, Next day, and Next-day Covert). FL exhibited evidence of day-to-day memory in the Next-day covert tests (black bars) and in her improved performance when the same scenes had been viewed across multiple days (compare the two white bars and the two black bars in the left panel).

In an interesting twist to the story, an intensive training program at Johns Hopkins University taught FL to sleep for 3.5 hrs at a time, at which point she could still retain the day's memories.

Initially, she was placed on a sleep deprivation protocol and remained awake for 36 h. There was no loss of memory during this period. The following day the treatment team initiated a regimen in which she was awakened after longer and longer periods of sleep each night. After 1, 2, 3, or 4 h of sleep she retained all memories, but after 6 h of sleep she had recurrence of her memory loss. Thus, she was able to tolerate up to 4 h of continuous sleep without memory loss for the previous day's events.

To conclude, the Baxendale (2004) quote above is correct in asserting that "movie amnesia", in which the protagonist loses all past autobiographical memories and a sense of identity, is unlike what occurs with brain damage in the real world. And 50 First Dates is even further off the mark. But sometimes, life imitates art... or an average Adam Sandler movie.

The insula (originally called the “island of Reil”) is emerging from its hiding place inside of the human brain. It is easy to find articles and textbooks which show the lateral aspect of the brain but barely mention the insula, if at all (http://www.ninds.nih.gov/disorders/brain_basics/know_your_brain.htm) or treat it as a deep brain structure, like the amygdala (http://www.scientificamerican.com/article.cfm?id=faulty-circuits). In fact, in Brodmann’s famous map of cortical cytoarchitectonic areas, it was not even worthy of a number! [See Kurth et al. 2009, PMID: 19822572; Brodmann (1909) described only a posterior granular and an anterior agranular region in the human insular cortex.] Older neuroscientists remember the insula as a portion of the visceral brain, based on prominent writings by Penfield, Mesulam, Saper, and others (Penfield and Faulk 1955; Mesulam and Mufson 1982; Saper 2002); some investigators simply call it a multi-modal region and cite the brief reviews by Augustine (1985, 1996); but for many new investigators who find it unexpectedly activated in their functional imaging study, it is simply an enigma.

In order to provide an overview of this vast literature for a 2009 opinion article (Craig 2009), I compiled reports from disparate and unfamiliar branches of neuroscience. To my mind, this burgeoning literature compelled the hypothesis that the anterior insula engenders human awareness, yet only one article had directly addressed this possibility (Klein et al. 2007), and an astonishing number of authors had reported strong activation of the insula without comment. The immediate need for an anthology became obvious, in which leading primary investigators from these disparate fields could re-appraise the role of the insula in light of the new perspective provided by this extraordinary convergence of evidence.

The overall goal of this set of articles is to provide a solid starting point for new investigators by identifying the issues and the opportunities for advances in our knowledge of this unique portion of the human brain. The authors were encouraged by the peer reviewers and the editors to be thorough and prospective, and to express their individual viewpoint as lucidly as possible. We hope that young neuroscientists will find fertile ground here. Indeed, we are all excited by the prospects for awe-inspiring discoveries in the convergence of these disparate fields of neuroscience.

For sheer volume you have to include the insula. From 1985-2009 there was a total of 197,256 articles (compare to 82,438 for the hippocampus). The number of PubMed hits for insula in 1985 was 3,906; in 2008 it was 13,375.

Tuesday, June 01, 2010

In Short Cuts, the "vegetarians and vegans are more empathetic" neuroimaging article was mentioned in passing, but I didn't actually blog about it. However, there has been one thing [OK, more than one thing] bothering me about this paper...

But first, a quick summary of the Methods which were rather straightforward.

Filippi and colleagues (2010) recruited 20 omnivores, 19 vegetarians, and 20 vegans to participate in a study that examined their brain responses to images of human and animal suffering. They were naïve as to the goals of the experiment. Before entering the scanner, all participants completed the Empathy Quotient, a 40 item questionnaire [plus 20 filler questions] that rates one's level of empathy (Baron-Cohen & Wheelwright, 2004). The omnivores did indeed have lower EQ scores (38.8) than the vegetarians (49.5) and the vegans (44.6), who did not differ from each other.

...vegetarians and vegans have constantly an higher engagement of empathy related areas while observing negative scenes, independently of the species of the individuals involved, which is characterized by an increased recruitment of the ACC and the IFG. Increased activation in the ACC and left IFG in vegetarians and vegans during human and animal suffering view is likely to reflect a stronger empathic response in the first two groups.

Remarkably, the within-group analysis during animal picture view, showed the absence of signal changes (in terms of activations and deactivations) within the amygdala in vegetarians and vegans, suggesting a down-regulation of amygdala response from areas located in the frontal lobes, in an attempt to regulate emotion through cortical processes in these subjects.

Why would the vegetarians and vegans attempt to down-regulate their emotional responses to animal suffering? And why would the vegans show greater amygdala responses to human suffering than did the omnivores and vegetarians??

Figure 4. Interactions between stimuli (animal/human) and groups (omnivore/vegetarian/vegan). (A) An interaction was found in the right amygdala, indicating greater increase to animal negative valence picture view in omnivores and to human negative valence picture view in vegans. An interaction between “human pictures” and “vegan group” was also found in the left amygdala.

The control condition consisted of “neutral” scenes that did not include living beings, faces, or suffering of any kind.

Participants passively viewed the photos, they did not have to respond by indicating their emotional reactions.

Participants could be desensitized to human suffering by watching the news.

One of the greatest issues, in my view, is with the mode of stimulus presentation. The event-related design (which is usually preferable) may not have allowed adequate time between pictures to "recover" from the shock of seeing a mutilated human or animal. If this were especially true for vegetarians and vegans viewing images of animal suffering, it could explain the curious silence of the amygdala. In such scenario, a blocked design (presenting all stimuli of one category in blocks, rather than intermixed) might have been a better idea.

The vegetarians and vegans in this study all made their dietary choices for ethical reasons. It is quite conceivable that they differed from the omnivores on any number of other dimensions. For example, evolutionary psychology extremist Satoshi Kanazawa recently blogged about Why Vegetarians Are More Intelligent than Meat Eaters, but this only held for a UK sample born in 1958, but not for a US sample born between 1974 and 1983. In addition, some militant vegan PETA-types condone violence against scientists performing animal experiments, so one could expect their responses (and empathy) towards human suffering to be diminished [NOTE: empathy scores were numerically lower for vegans than for vegetarians].

It would be interesting, then, to compare these "ethical" sorts to others who have chosen to be vegetarian or vegan for heath reasons, such as familial hypercholesterolemia or athletic competitions such as the triathlon.

About Me

Born in West Virginia in 1980, The Neurocritic embarked upon a roadtrip across America at the age of thirteen with his mother. She abandoned him when they reached San Francisco and The Neurocritic descended into a spiral of drug abuse and prostitution. At fifteen, The Neurocritic's psychiatrist encouraged him to start writing as a form of therapy.